Academic literature on the topic '(1796 Aug. 19)'

Abstract To determine the daily and total energy expenditures of breeding female House Sparrows (Passer domesticus), we collected 276 females near London, Ontario between April 1981 and May 1983. Protein and fat content of developing follicles, eggs, and oviducts were determined and converted into their energy equivalents. Eight days were required to develop and lay a modal clutch of 4 eggs. Fat energy requirements were not estimable accurately because total body fat did not decline linearly over the egg production period; therefore, energy requirements were estimated as a range. Based on a 4-egg clutch, the maximum daily costs of reproduction, 16.5-17.6 kJ/day, equalled 44-47% of a female's standard metabolic rate. We estimate that daily costs very less than 10% for other clutch sizes (3 or 5). The total energy demand of reproduction was 66-71 kJ. Protein requirements comprised 59-63% of the total costs and were apportioned among oviduct (5-6%), yolk protein (17-19%), and albumen (36-39%). Fat requirements accounted for the remaining 37-41% of total costs. Based on our estimates of energy needed for reproduction, and on other evidence, we suspect that egg production by House Sparrows is not constrained by energy acquisition.

Abstract Introduction Relapse, graft-versus-host disease (GvHD) and associated non-relapse mortality are the main obstacles to successful hematopoietic stem cell transplantation in children with leukemia. αβ T cell depletion was developed to prevent GvHD and improve immune reconstitution in recipients of mismatched grafts. Most current protocols use rabbit anti-thymocyte globulin (ATG) as an essential component of preparative regimen to secure engraftment and GVHD control. In order to avoid damaging effects of circulating ATG on graft NK and gd T cells, we have replaced ATG with pharmacologic blockade of IL-6 and CD80/CD28 co-stimulation axis in our ongoing study. Patients and methods Major transplantation outcomes were compared between participants of the current prospective trial (ATG-) and a retrospective control group (ATG+). A total of 165 children with acute leukemia (67 AML, 98 ALL, 68 female, 97 male, median age 8,7 y) underwent allo HSCT between 01.11.2013 and 01.03.2018. Of them 134 - from haploidentical donor and 31 from unrelated donor. All pts were in complete remission (CR1=80, CR2=67, CR>2=18). Ninety-two pts received treosulfan-based conditioning, 73 - TBI-based (all ALL). Either melphalan (n=46) or thiophosphamide (n=98) or etoposide (n=21) were added as a second agent. Fludarabine was used in all pts. Two types of GVHD prophylaxis were used: type 1 (ATG+), (n=98): thymoglobulin 5mg/kg, rituximab 200mg/m2 with either bortezomib on days +2, +5 (n=72) or tacro (n=9) or without any additional agents (n=17); Type 2 (ATG-) (n=67): tocilizumab at 8 mg/kg on day -1, bortezomib on day +2, +5 with abatacept at 10 mg/kg on day -1, +7, +14, +28 (n=63) or without added agent (n=4). αβ T cell depletion with CliniMACS was used in all cases. The median dose of CD34+ cells was 9x106/kg, αβ T cells - 16 x103/kg. Modified (CD45RA-depleted) donor lymphocyte infusions (DLI) were administered to 113 pts. Twenty-five patients received DLI on day 0 and 88 pts received DLI after engraftment. Median time of follow-up for survivors was 2 years (range, 0,3 - 4,5). Results Three patients died before engraftment due to septic event. Primary engraftment was achieved in 161 of 162 evaluable pts (99,3%), the median time to neutrophil and platelet recovery was 16 and 15 days. Among the whole cohort the cumulative incidence of acute graft-versus-host disease (GvHD) grades II - IV and III - IV was 11,5% (95% CI: 7,5-17,6) and 4,8% (95% CI: 2,5-9,5) respectively. The cumulative incidence of cGvHD was 10 % (95% CI: 6,3-15,9). The incidence of aGvHD and cGvHD was not different between ATG (+) and ATG (-). Among the whole cohort 2-year pTRM was 8% (95%CI: 4,8-13,5). pTRM was significantly lower among ATG (-) group - 1,5% (95%CI:0,2-10,4) versus 12,2% (95%CI:7,2-20,8) among ATG (+) group, p = 0,015. The cumulative incidence of relapse at 2 years was 21% (95%CI: 15,5-29), 24% (95%CI: 16-35), among ATG (+) and 19% (95%CI: 11-32), among ATG (-), p = 0,8. Two-year pEFS was 70% (95%CI: 62-77), 2-year pOS - 78% (95%CI: 71-85). Among patients, who received ATG (-) regimen, pEFS was 76% (95%CI: 68-89), as compared to 65% (95%CI: 56-75) among ATG (+), p=0,1 and pOS was 89% (95%CI: 81-97) versus 72% (95%CI: 63-81), p=0,032, respectively. αβ T cell recovery at day +30 was associated with a trend to decreased incidence of relapse, CI of relapse was 32% (95% CI:22 - 47) in those with αβ-T cell count < median vs 18 % (95% CI: 11-32) in those with αβ-cell count >median, p=0,08. EFS among αβ T" high" was 81% (+/-10) vs 56% (+/-14) among αβ T"low", p=0,002. Discussion We confirm that the depletion of αβ T cells from the unrelated and haploidentical graft in combination with intensive conditioning regimen ensures high engraftment rate and low transplant-related mortality. Our analysis suggests that polyclonal ATG serotherapy is not an essential part of the transplant regimen in αβ T-depleted transplantation. Combined administration of tocilizumab and abatacept after αβ T cell-depleted grafting effectively prevents GVHD, does not compromise engraftment, appears to decrease non-relapse mortality and improve survival. Disclosures No relevant conflicts of interest to declare.

From May to June 2011, during a survey of the wheat-growing areas in Meknes in the Saïs Region of Morocco, several cyst nematode populations were detected. Sampling was performed 1 month before wheat (Triticum durum) harvest, in fields showing patches of stunted plants. Plants were growing poorly, had chlorotic lower leaves, and a reduced numbers of ears. Root systems were short and had a bushy appearance because of increased secondary root production. No cysts were visible on the roots, but were found in the soil. Cysts were collected from soil on 200-μm sieves by the modified Cobb decanting and sieving method (1) and identified by morphology and internal transcribed spacer (ITS)-rDNA sequencing. All isolates were identified as Heterodera avenae except the isolate from Aïn Jemâa. From the latter, key morphological features from cysts and second-stage juveniles (J2) were determined. The cysts (n = 10) had the following characteristics: bifenestrate vulval cone, body length without neck 590 μm (551 to 632 μm), body width 393 μm (310 to 490 μm), neck length 75 μm (65 to 90 μm), fenestra length 64 μm (60 to 72 μm) and width 21 μm (18 to 25 μm), underbridge length 96 μm (85 to 115 μm), vulval slit length 8 μm (7 to 9 μm), vulva bridge width 27 μm (24 to 33 μm), and bullae absent. The J2s (n = 10) had the following characteristics: body length 445 μm (412 to 472 μm), body width 19 μm (19 to 21 μm), stylet length 24 μm (23 to 25 μm), four lateral lines, tail length 50 μm (46 to 54 μm), and hyaline terminal tail 28 μm (24 to 31 μm). Values of the morphological characters were within the range of H. latipons reported by Handoo (3). The bifenestrate cysts with a strong underbridge and no bullae and J2 with a tail length greater than 40 μm, a stylet longer than 15 μm, and four incisures in the lateral field were typical for H. latipons. To confirm the identification, molecular observations were made. DNA was extracted from three juveniles from three different cysts separately (4). The ITS-rDNA region was amplified using the primers 5′-CGT AAC AAG GTA GCT GTA G-3′ and 5′-TCC TCC GCT AAA TGA TAT G-3′ as described by Ferris et al. (2). This resulted in a 1,040-bp DNA fragment. The PCR-products were purified and sequenced (Macrogen, Inc., Seoul, Korea). All sequences obtained (GenBank Accession Nos. per cyst: JQ319035, JQ319036, and JQ319037) were compared with sequences available from the GenBank database ( www.ncbi.nlm.nih.gov ), including several species of Heterodera. This comparison revealed a sequence similarity of 97 to 99% with H. latipons and 89% or lower with any other species of Heterodera. Morphological and molecular identification demonstrated that the population of cyst nematodes from a wheat field in Aïn Jemâa, Morocco was H. latipons. In the patches with poor growing plants, 65 cysts per 100 cm3 soil were found. To our knowledge, this detection represents a new record of H. latipons. Since the nematode can cause considerable damage to wheat, one of the main cereals produced in Morocco, care should be taken to prevent the spread to other regions. References: (1) K. R. Barker. Page 19 in: An Advanced Treatise on Meloidogyne. Vol II. Methodology. C. C. Carter and J. N. Sasser, eds. North Carolina State University Graphics, Raleigh, 1985. (2) V. R. Ferris et al. Fundam. Appl. Nematol. 16:177, 1993. (3) Z. A. Handoo. J. Nematol. 34:250, 2002. (4) M. Holterman et al. Mol. Biol. Evol. 23:1792, 2006.

Abstract Since 2000, daunorubicin (DNR) 60 mg/m²/d for 3 days combined with cytarabine 200 mg/m²/d CIV over 7 days is the standard induction regimen used by the french GOELAMS group for younger patients treated for AML. Recently, use of high dose DNR (90 mg/m²/d for 3 days) results in higher complete remission (CR) rate and better survival as compared with DNR 45 mg/m²/d for 3 days (Lowenberg, NEJM, 2009, Fernandez, NEJM, 2009). To date, no prospective data are available comparing DNR 60 mg/m²/d and 90 mg/m²/d for induction therapy. In this retrospective study, we report the outcome of 402 consecutive patients treated with either intensified induction (DNR90) or standard DNR60 regimen. Selection criteria were age<=60 years; APL and CBF AML were excluded; induction course with either DNR 60 mg/m² (DNR60 or 90 mg/m² DNR90; day-15 bone marrow blast evaluation at day 15 and for CR. All patients were treated consecutively between Jan 2000 and Aug 2012 in 2 French centers, DNR dose allocation was based on treatment period (DNR90 since 2010). Treatment followed GOELAMS LAM-2001 protocol schedule (Lioure, Blood, 2012). Briefly, patients received second induction course if they presented with more than marrow 5% blast at day-15 examination. Once in CR, 2 to 3 high-dose cytarabine consolidation courses were planned. All patients with matched related or unrelated donor were scheduled for transplant after 2 consolidation courses. A total of 402 patients were analyzed (340 treated with DNR60 and 62 with DNR90 respectively). Median age was 49 years (range: 16-60), median WBC was 7.2 G/L (range: 0.1-430), 76 (19%) had secondary AML (therapy related AML or acute transformation of a myelodysplastic syndrome) and 108 (27%) had unfavorable cytogenetics. Patient and disease characteristics were well balanced between DNR90 versus DNR60 except for higher WBC for DNR90 group (median 6.6 vs. 17.6, p=0.021). At day-15 marrow evaluation, 135 DNR60 patients (40%) and 23 DNR90 patients (37%) had more than 5% marrow blast, (p=0.406). Second induction course was given in 122 (36%) and 22 (35%) DNR60 and DNR90 patients respectively (p=0.489). CR was achieved in 244 (72%) and 46 (74%) in DNR60 and DNR90 patients respectively (p=0.412) while 266 DNR60 patients (78%) and 54 DNR90 patients (87%) achieved at least CRi (p=0.073). Induction death rate was similar between the 2 groups (2% vs. 5%, p=0.148). Median FU was 72 vs. 21 months for DNR60 vs. DNR90 respectively (p<0.001). Two-years Overall survival (OS) probability was 52% and 60% in DNR60 and DNR90 group respectively (p=0.329) (Figure 1). In the 320 patients achieving at least CRi after induction therapy, 2-years relapse-free survival (RFS) probability was 48% and 53% in DNR60 and DNR90 groups respectively (p=0.714) (Figure 1). In multivariate analyses, secondary AML, unfavorable cytogenetics, day-15 bone marrow blast => 5%, and WBC => 100 G/L were associated with shorter OS while only unfavorable cytogenetic abnormalities and WBC => 100 G/L adversely influenced RFS. In conclusion, we found that induction therapy based on daunorubicin at the dose of 60 mg/m² or 90 mg/m² were comparable for CR rate, OS, and RFS. This suggests that DNR60 might be equivalent to DNR90 that has recently been established as a standard of induction chemo for AML. Prospective trials are needed to confirm these findings. Disclosures: Prebet: CELGENE: Honoraria.

Abstract Background: Clostridium difficile infection (CDI) is the leading cause of hospital-acquired diarrhea. The incidence of CDI in patients hospitalized for stem cell transplant (SCT) is much higher than in other inpatients, reaching between 12.5-30%. Antibiotic exposure, duration of hospitalization, and acute graft-versus-host disease (aGVHD) can contribute to the increased incidence of CDI. The incidence of CDI and risk factors associated with its development after cord blood transplant (CBT) have not been well-studied. Methods: Ninety-five patients who received CBT at Vanderbilt University Medical Center from 2002 to 2013 were retrospectively reviewed. CDI was diagnosed using a stool toxin assay prior to 2011; DNA testing was used after 2011. CBT patients with CDI were compared to patients without CDI. Results: Of 95 CBT patients, 34 (37.8%) developed CDI. Thirty day cumulative incidence of CDI was 37%. Comparative data on CDI incidence at our institution for general adult inpatients is being collected. Pre-transplant characteristics of patients are shown in Table 1 and transplant characteristics are shown in Table 2. There was no significant difference in incidence of aGVHD in patients with CDI (76.5%) and without CDI (59%). CDI was diagnosed in 41.6% (25/56) of patients with aGVHD who received systemic steroids and only in 23% (9/39) of patients with aGVHD who did not receive systemic steroids (P<0.05). Time (mean) to CDI (with death due to other causes as a competing risk) was shorter in patients receiving systemic steroids (80 days vs. 90 days, P<0.05). Among patients who received systemic steroids, CDI-infected patients had received higher dosages (mean 1.68 mg/kg vs. 1.28 mg/kg, P<0.05). There was no difference in incidence of CDI based on antibiotic exposure, type of antibiotic use, number of episodes of bacteremia, GI aGVHD, and recurrence of aGVHD (data not shown). Diagnostic modality (toxin assay vs. DNA testing) did not impact the CDI incidence rate. Using Cox-proportional hazards model, peak dose of steroids was an independent predictor of CDI (HR=2.42, 95% CI 1.02-4.01, p<0.05). Conclusions: Our study shows that CDI is an important infectious complication of CBT with an incidence of 37%. CDI patients were more likely to have received systemic steroids for aGVHD, and at higher dosages. The connections between CDI, steroids, and aGVHD need to be explored further. Strategies to prevent CDI in this high-risk group need to be developed. Table 1: Pre-transplant characteristics of patients with and without Clostridium difficile infection (CDI) CDI (N=34) No CDI (N=61) Age, y, mean (range) 21 (3 mo-57 y) 28 (6 mo-65 y) Gender, n (%) Female 19 (55.9) 29 (47.5) Male 15 (44.1) 32 (52.5) Race, n (%) African American 9 (26.5) 15 (24.6) Caucasian 20 (58.0) 37 (60.7) Hispanic 3 (8.8) 5 (8.2) Other 2 (5.9) 4 (6.5) Diagnosis, n (%) Acute leukemia 23 (67.6) 28 (45.8) Other leukemia 0 (0) 3 (4.9) Lymphoma 5 (14.7) 5 (8.2) Myeloid disorders 3 (8.8) 17 (27.9) Other 3 (8.8) 8 (13.1) Risk status, n (%) Low 7 (20.6) 19 (31.1) Intermediate 12 (35.3) 11 (18.0) High 12 (35.3) 27 (44.3) Table 2: Transplant characteristics of patients with and without Clostridium difficile infection (CDI) CDI (N=34) No CDI (N=61) Type of transplant, n (%) Single unit 19 (55.9) 29 (47.5) Double unit 15 (44.1) 32 (52.5) Cell dose, mean, range 6.3 (0.7-27.3) 5.7 (1.7-16.1) Recipient CMV seropositive, n (%) 19 (55.9) 28 (45.9) Total body irradiation, n (%) 29 (85.3) 51 (83.6) Conditioning intensity, n (%) Ablative 24 (70.6) 40 (65.6) Non- ablative 10 (29.4) 21 (34.4) Use of ATG, n (%) 16 (47.1) 24 (39.3) GVHD prophylaxis, n (%) Mycophenolate mofetil 29 (85.3) 55 (90.2) Calcineurin inhibitors 34 (100) 61 (100) Duration of neutropenia, days, mean (range) 21.6 (7-37) 23 (9-49) Acute GVHD, n (%) 26 (76.5) 36 (59.0) Type of acute GVHD, n (%) Skin 13 (38.2) 24 (39.3) GI 19 (55.9) 23 (37.7) Liver 0 (0) 3 (4.9) Systemic steroids received for acute GVHD*, n (%) 25 (73.5) 31 (50.8) Steroid dose received for acute GVHD*, mean in mg/kg 1.68 1.28 Survival, n (%) Alive 16 (47.0) 34 (55.8) Deceased Disease 6 (17.6) 12 (19.7) Infection 9 (26.5) 11 (18.0) GVHD 2 (5.9) 1 (1.6) Other 1 (2.9) 3 (4.9) *indicates statistical significance with p<0.05 Disclosures No relevant conflicts of interest to declare.

Abstract CD34 selected stem cell transplants (SCT) have shown similar survival rates as unmodified SCT, with lower incidence of acute and chronic graft-versus-host disease (GVHD). A common conditioning regimen for patients with advanced myelodysplastic syndrome (MDS) undergoing CD34 selected SCT is a combination of busulphan, melphalan, fludarabine, and anti- thymocyte globulin (ATG). The ideal area under the curve (AUC) and overall dose intensity of busulphan is unknown in these pts. We aimed to study the relationship between busulfan AUCs and transplant outcomes in this pt population. This retrospective analysis included 68 pts with advanced MDS (RAEB-I and higher) who underwent CD34 selected SCT between 2000-2012. Median age was 58.05 yrs (26-73). There were 36 women (52.9%). HCT CI was ³ 3 in 37 pts (54.4%). MDS subtype at diagnosis by WHO criteria was: RA/RCMD-19 (all progressed to RAEB/AML), RAEB-I 20 &RAEB II 29; and by IPSS-R criteria in 65 pts: very low risk-4, low risk-9, intermediate risk-14, high risk-20 & very high risk-18. All pts were conditioned with busulphan IV 0.8 mg/kg dose, melphalan 140 mg/m2, fludarabine 125 mg/m2 & ATG . Thirty-nine pts received 10 doses of busulphan and 29 pts 12 doses. The dose was increased to reduce the relapse rate. Pharmakokinetic studies were done after first busulphan's dose and based on results adjustments were made to achieve a target dose of 1025-1315µM x min. G-CSF mobilized donor peripheral blood stem cells underwent CD34+ selection and depletion of T cells using CliniMACS immunomagnetic selection columns (Milteny Biotec). Donors were HLA matched, 48 (18 related & 30 unrelated) or mismatched unrelated, 20. The median first-dose busulphan AUC was 1,206 (723-2,180). In 27 pts (39.7%) this was within target range of 1,025-1,315 with 16 pts (23.5%) below and 25 (36.7%) above. The median total busulphan exposure for all pts was 12,822 (9,513-15,754), with 1st quartile range of 9,513-12,181 and 4th quartile range of 13,664-15,754. The median total exposure in the 10 doses group (group 10) was 12,520 (9,513-15,754) and in the 12 doses group (group12) 13,420 (9,860-15493). The 2-years overall survival (OS) was 61.5% (CI 44.5-74.7) in group 10 and 55.2%(35.6-71) in group 12 and 2-years relapse free survival (RFS) was 56.4% (39.6-70.2) in group 10 and 51.7% (32.5-67.9) in group 12. The 2-years cumulative incidence of relapse was 15.4% (CI 3.9-26.9) in group 10 and 13.8% (CI 0.9-26.6) in group 12. The non-relapse (NRM) mortality at 2 years was 28.2% (13.8-42.6) in group 10 and 34.5% (16.7-52.2) in group 12. aGVHD grade II-IV was 12.8% (2.2-23.5) in group 10 vs 23.1% (6.5-39.7%) in group 12. None of these differences were statistically significant. Further analysis by quartiles showed no differences in OS, RFS, relapse and NRM between the 4 groups. However, grade II-IV acute GVHD was significantly higher in the 4th quartile exposure, 35.6% (8.9-62.3) vs 5.9% (0-17.5), 11.8% (0-27.6) and 17.6% (0-36.4) in the 1st, 2nd and 3rd quartiles (p=0.046) (table 1). In thishomogenous cohort of pts, total busulphan exposure was only found to be associated with grade II-IV aGVHD, with higher incidence seen in pts who had exposure >13,664. Donor mismatch status was not associated with higher aGVHD in this cohort and therefore can not explain the increased aGVHD seen with higher busulphan exposure. A trend for better transplant outcomes was seen with total exposure of 12,182- 13,663 (2nd and 3rd quartiles); though the differences were not statistically significant. In CD34 selected allo-HSCT for pts with advanced MDS, the intensity of the conditioning has an impact on transplant outcomes and therefore determining the range of busulphan that offers best survival with minimal GVHD has important clinical implications. Table 1. Transplant outcomes (cumulative incidence with 95% CI): Total exposure 6-months CI ofaGVHD II-IV 2-year CI of Relapse 2-year CI NRM 2-year CI OS 2-year CI RFS Q1: 9,513-12,181, n=17 5.9 (0-17.5) 35.3 (11.6-59) 23.5 (2.4-44.7) 52.9 (27.6-73) 41.1 (18.6-62.6) Q2: 12,181-12,822, n=17 11.8 (0-27.6) 11.8 (0-27.7) 23.5 (2.6-44.4) 70.6 (43.1-86.6) 64.7(37.7-82.3) Q3: 12,823-13,663, n=17 17.6 (0-36.4) 5.9 (0-17.5) 35.3 (11.7-58.9) 58.8 (32.5-77.8) 58.5 (32.5-77.8) Q4: 13,664-15,754 n=17 35.6 (8.9-62.3) 5.9 (0-17.4) 41.2 (16.8-65.6) 52.9 (27.6-73) 52.9 (27.6,-73.0) p value* overall: 0.185, Q4 vs others: 0.046 0.221 0.409 0.663 0.540 Figure 1. Figure 1. Disclosures Giralt: SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding.

Abstract Busulfan, an important agent used in conditioning regimens before hematopoietic stem/progenitor cell (HSPC) transplantation, has a “narrow” therapeutic index. Targeted dosing of busulfan based on its pharmacokinetic (PK) profile is often used. We studied the age-dependent PK profile of single daily dose intravenous Bu (IV Bu) in pediatric patients and determined a target range of Bu exposure that is appropriate for children undergoing reduced-intensity conditioning (RIC) HSPC transplantation. The RIC regimen included: fludarabine 30 mg/m2 per day for 6 days (days –10 to –5); single daily treatment doses of IV Bu given over 3 hours each day for 2 days (days –5 and –4), with individualized Bu dosing based on the PK results of a test dose; and rabbit ATG (2 mg/kg/day) or equine ATG (40 mg/kg/day) for 4 days (days –4, –3, –2 and –1). In 2 variations of the regimen, ATG was either eliminated or replaced with extracorporal photopheresis. Allogeneic HSPC were infused on day 0. Cyclosporin A and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. An initial cohort of 52 patients was studied. The median age of the cohort was 7.7 years (range 0.06–17.6), with 19 patients less than 4 years of age (group 1) and 33 patients older than 4 years (group 2). Patients had either malignant or non-malignant diseases (immunodeficiency (n=14), metabolic disease (2), marrow failure (6), histiocytosis (1), ALL (9), AML (5), CML (4), MDS (2), lymphoma (5)), neuroblastoma (4)). Patients received a test dose of IV Bu (0.8 mg/kg) five days before the treatment doses. After the test dose, the median AUC attained was 886 μM·min in group 1 (range 439–1828) and 965 μM·min in group 2 (range 579–1970). Only 59% of the patients in both groups attained a plasma concentration-time “area-under-the-curve” (AUC) within the expected range of 800–1200 μM·min. Based on the test dose PK, patients received individualized treatment doses adjusted to target an AUC of 4000 μM·min per day for 2 days (range 3200–4800 μM·min). The median daily treatment dose of IV Bu given was 3.45 mg/kg in group 1 (range 0.8–7.2) and 3.20 mg/kg in group 2 (range 0.9–5.4), with a distinct and linear inverse-relationship between the weight-normalized treatment dose required and the weight of the patient (treatment dose = 4.0 mg/kg - 0.01*weight in kg, p=0.001). After the adjusted treatment dose, patients who achieved AUC within the targeted range increased to 67% in group 1 and 84% in group 2. Despite the dose adjustment, group 1 attained a lower median treatment dose AUC (3568 μM·min) as compared to group 2 (4035 μM·min) (p=0.001). All patients in this cohort tolerated the conditioning regimen. No patient developed seizures or hepatic veno-occlusive disease. Stable donor chimerism, however, was achieved in only 56% of patients in group 1 and 79% in group 2. Eight patients received a second transplantation because of primary or secondary graft failure. Eight patients died of transplantation-related causes. Because of the concern that a low AUC correlated with an adverse clinical outcome, a second cohort of 23 patients followed a modified protocol in which a treatment dose AUC of 5000 μM·min was targeted (range 4200–5800 μM·min). The median age of the second cohort was 2.1 years (range 0.3–21), with 13 patients less than 4 years and 10 patients older than 4 years. The median daily treatment dose given in this cohort was 4.5 mg/kg (range 2.6–6.5). All patients tolerated the higher Bu treatment dose with minimal regimen-related toxicity. After the treatment dose, patients attained a higher median AUC of 4825 μM·min (range 3719–5900), with over 90% of the patients achieving AUC within the targeted range of 4200–5800 μM·min. The number of patients who achieved stable donor chimerism also increased to 91%. One patient died of a transplantation-related cause. In conclusion, our results showed that RIC regimens utilizing 2 single daily doses of IV Bu were effective and well tolerated in children. An age-dependent variability in the PK profile of IV Bu could have contributed to a higher rate of graft failure in the younger patients after they received the Bu doses targeted to achieve an AUC of 4000 μM·min per day. Since there appears to be a wide safety margin in the upper limit of the Bu therapeutic range in RIC transplantation, a targeted AUC of 5000 μM·min per day for two days is recommended in pediatric patients, especially those less than 4 years of age.

Abstract Background: Epidemiological data on MDS is scarce in France, and registries from other countries do not provide data on the daily practice management of MDS in 2008. Methods: GFM centers were asked to collect characteristics of ongoing or recent treatments in all MDS patients (pts) seen at their clinic (as in or outpatients) during the Jan 28th–Feb 3rd, 2008 period (one week).Results: 919 pts from 74 centers were included, 57% males, mean age (+/− SD), 73 (±11) years, with 2.8%, 19% and 28% of pts aged &lt;50, &lt;65 and &gt;80 years, respectively (resp).13% of pts were hospitalized &gt;24h (4.5% for infections or bleeding and 8.5 % for “active” treatments), 46% were seen in the day care facility (40% for transfusions), and 41% as consultations (for staging, follow up or ambulatory treatment). 93% of patients had PS ≤2. Median interval from diagnosis to survey was 29.2 months. FAB at time of survey was: 35.1% RA, 18.5% RARS, 39.1% RAEB, 7.4% CMML; WHO was: 17.4% RA, 13.3% RARS, 14% RCMD, 4.5% RCMD-RS, 18.5% RAEB-1, 15.9% RAEB-2, 7.7% CMML, 4.9% 5q-syndrome and 3.9% unclassifiable. Cytogenetic analysis had been performed at least once in 77.4 % pts: favorable (498 pts), intermediate (88 pts), unfavorable (96 pts). IPSS (determined in 75.4% of pts) was: 41.6% low, 33.3% Int-1, 16.4% Int-2 and 8.7% high. Significant differences between pts &lt;65 years and &gt;65 years were, respectively, % of unfav karyotype (25.8% vs. 12.7%, p=0.0004), of isolated +8 (5.1% vs. 2.1%, p=0.04), of isolated −7 (6.2% vs. 1.1%, p=0.0003), and, with borderline significance, of CMML (4.5% vs. 9.5%, p=0.06), of 5q-syndrome (1.5% vs. 5%, p=0.07). EPO level, assessed in 359 (39.1%) of pts at diagnosis and 252 (27.4%) of pts at time of survey) was &gt;200UI/l in 24.5% and 26.6% resp, and &gt;500U/l in 13.5% and 14.7% pts resp and was significantly correlated with interval from diagnosis. At the time of survey, treatment received in the last 6 months (IPSS: high-int 2 vs low–int1) included: no active treatment 66.5% (IPSS: 42% vs. 72.9%), chemotherapy 12.8% (IPSS: 22.6% vs. 9.1%) including 2.7% intensive and 0.7% LD AraC, allogeneic SCT 1.7% (IPSS: 3.8% vs. 2.6 %) including 0.3% classical and 1.4% NMA, azacytidine 6.5%, (IPSS: 21.6% vs. 2.3%), decitabine 0.8%, lenalidomide 4%, thalidomide 0.5%, ATG 0.2 %, androgens 2.2% while 64.8% pts required RBC transfusions (IPSS: 81% vs. 61%) and 39.7% pts received an Erythropoiesis-Stimulating Agent (ESA) (IPSS: 40.3% vs. 37.2%), alone in 314 pts (epoetin alfa or beta in 92 pts, darbepoetin in 222 pts), and with G-CSF (61 pts). Response rates to ESAs were 58.6% and 33.8% in low int-1 and int-2-high risk MDS, resp (p=0.0009). Iron chelation therapy was administered in 17.6% pts (5.8% desferroxamine, 11% deferasirox) including 22.1% and 13.6% low-int-1 and int-2-high risk MDS, resp (p=0.009). Conclusions: Our survey provides a better knowledge of the characteristics and of the daily management of MDS in France. Of particular note are the more frequent unfavorable karyotypes in MDS pts &lt;65 years and the generally low EPO levels that may increase the indications for ESAs in low and int 1 risk MDS with anemia. Apart from ESAs, active treatments of MDS still only reach a minority of pts, and transfusions account for as many as 40 % of the hospital visits/stays for MDS.

Abstract Aims: Autologous stem cell transplantation (ASCT) is an important component in the treatment of newly diagnosed multiple myeloma (MM). However, relapse following ASCT is considered almost inevitable, with a median time to progression (TTP) of approximately 23-26 months (without maintenance) and 40-46 months (with maintenance)(Attal MA et al. N Engl J Med 2012; 366:1782-1791; McCarthy PM et al. N Engl J Med 2012; 366:1770-1781). However, some patients can experience a prolonged period of remission with ASCT. The purpose of this study was to identify and characterize patients who have an exceptional response to upfront ASCT without maintenance therapy, and to determine the frequency of relapse in such patients. Methods: We searched the Mayo Clinic Multiple Myeloma bone marrow transplant database for patients who were diagnosed with MM between Aug 1, 1988 to Jan 3, 2006, and underwent ASCT within 12 months of initial diagnosis. For the purposes of this study, we defined exceptional responders as patients who were free of progression for 96 months or more, which is 2-3 fold more than the median TTP expected in this population. Since maintenance therapy was not standard of care at the time, only a small minority (6) of patients with prolonged TTP had received maintenance therapy; these patients were excluded since the study was focused on exceptional response with ASCT alone. One patient who had a tandem autologous transplant was excluded. Results: 509 patients underwent transplant during the study period. Of those, 46 (9%) met criteria for exceptional response. Twenty seven (59%) were female, 19 (41%) were male. Median age was 57.28 years, range, 31.9-73.0. Of 45 patients with response data available, the best response status was complete response or better in 32 patients (73.3%), VGPR in 4 patients (8.9%), and PR in 8 patients (17.7%). FISH data were available during the disease course for 41 patients. Of these, the majority, 28 patients (68.3%), had no abnormalities detected by the probes used; 3 patients (7.3%) had high risk cytogenetics (t(4;14) in 2 patients and t(14;16) in one patient) , 4 (9.8%) had trisomies; 6 patients had other isolated abnormalities. At last follow up, 23 patients have progressed (50%); 14 (30.4%) have died, including one who died without progression to MM. The median overall survival from time of diagnosis of the exceptional responders was 18.5 years, range 9.2-22 years. From the landmark time of 96 months, the median TTP was 6.2 years, range, 0.4-10.6 years (Figure 1); No plateau was seen in the TTP curve. From the landmark time of 96 months, the median OS was 10.5 years, range, 0.4-14 years. Conclusions: We conclude that approximately 10% of patients with newly diagnosed myeloma have an exceptional response to a single ASCT without maintenance therapy. These patients have a remarkable overall survival, both from diagnosis and from the landmark time point where they are classified as having achieved an exceptional response. Although TTP from the landmark time point is excellent, with median TTP of 6.2 years, there appears to be no plateau in the curve indicating ongoing risk of relapse despite a prolonged period of disease stability. Exceptional responders tended to have normal FISH studies (likely an indicator of responsive, low-tumor burden disease), and nearly 20% achieved this state despite not attaining a complete response. Figure. Figure. Disclosures Gertz: Research to Practice: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; janssen: Consultancy; Teva: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Seismic status in Bangladesh has been investigated using earthquake data recorded by the global network of USGS during 1980 to 2016. Seismicity parameters such as magnitude completeness Mc, b-value and a-value are being estimated. It has observed that the overall b-value in and around Bangladesh is of 0.84 which is seemed to be seismically active zone. As, reliable b-value assessment can lead to better seismic hazard analysis, reliable magnitude of completeness Mc can lead to b-value assessment of an area, this work has dealt and estimated magnitude of completeness Mc using various techniques for the whole region for a reliable estimation. Estimated Mc is obtained to be around 3.9-4.7, which lead to b-value of 0.93. Spatial variations of Mc and b-value have been investigated for 1ox1o horizontal and vertical rectangular regions for the study area between 18-29°N and 84-95°E. Estimated Mc and b-value along with b-value are then averaged for the common regions in the pair of horizontal and vertical regions. Results are then being presented in the form of maps. The findings resemble as, the Mc is low at the border line of N-W Bangladesh, and a line from Cox’s bazaar to Sylhet through Hill tracts. Remain parts belong to the Mc value of 4.1-4.2, thus the b-value obtained is varying from 0.68 to 1.2, where, the value is higher at region in Chittagong and Barisal division that extends toward north through part of Dhaka to Sylhet and lower at Rajshahi, Rangpur and part of Khulna division, while a-value is varying from 5.0 to 7.2 mostly from west to east.ReferencesAbercrombie R.E., and Brune J.N., 1994. Evidence for a constant b-value above magnitude 0 in the southern San Andreas, San Jacinto, and San Miguel fault zones and at the Long Valley caldera, California. Geophys. Res. Lett., 21(15), 1647-1650.Aki K., 1965. Maximum likelihood estimate of b in the formula log N=a-b M and its confidence limits. Bull. Earthquake Res Inst., Tokyo Univ., 43, 237-239.Aki S., 1987. On nonparametric tests for symmetry. Ann. Inst. Statist. Math., 39, 457-472.Al-Hussaini T.M., 2006. Seismicity and Seismic Hazard Assessment in Bangladesh: Reference to Code Provisions. Meeting on Seismic Hazard in Asia ICTP, Trieste, Dec. 4-8.Amorese D., 2007. Applying a change-point detection method on frequency-magnitude distributions. Bull. Seismol. Soc. Am., 97(5), 1742-1749. Doi:10.1785/0120060181.Banglapedia, 2012. The National Encyclopedia of Bangladesh. http://en.banglapedia.org/index.php?title=Tectonic_Framework, retrieved on 31 Aug 2017.Cao A.M., and Gao S.S., 2002. Temporal variations of seismic b-values beneath northeastern Japan island arc. Geophys. Res. Lett., 29(9), 481-483. Doi:10.1029/2001GL013775.Das R., Wason H.R., and Sharma M.L., 2012. Temporal and spatial variations in the magnitude of completeness for homogenized moment magnitude catalogue for northeast India. J. Earth Syst. Sci., 121(1), 19-28.Felzer K.R., 2008. Simulated aftershock sequences for a M 7.8 earthquake on the southern San Andreas fault. Seismol. Res. Lett., 80, 21-25.GSB, 2018. Seismic Zone Map of Bangladesh. http://gsb.portal.gov.bd/sites/default/files/files/gsb.portal.gov.bd/common_document/a6e75ad2_5acd_4fe3_911d_c9d25a7e349e/BD_Sciesmic-zonemap(NBC).pdf, retrieved on 31 March 2018.Gutenberg B., and Richter C.F., 1944. Frequency of earthquakes in California, Bull. Seismol. Soc. Am., 34, 184-188.Gutenberg B., and Richter C.F., 1956. Earthquake magnitude, intensity, energy and acceleration (second paper). Bull. Seismol Soc. Am., 46(2), 105-145.Hafiez H.E.A., 2015. Estimating the magnitude of completeness for assessing the quality of earthquake catalogue of the ENSN. Egypt. Arab J. Geosci., 8(1), 9315-9323. Doi:10.1007/s12517-015-1929-x.Hunting Geology and Geophysics Ltd., (1981), Interpretation and Operations report on an aeromagnetic survey in Bangladesh, Borehamwood, Hertfordshire, England.Iwata T., 2008. Low detection capability of global earthquakes after the occurrence of large earthquakes: investigation of the Harvard cmt catalogue. Geophys. J. Int., 174(3), 849-856. Doi:10.1111/j.1365-246X.2008.03864.x.Kagan Y.Y., 2002. Seismic moment distribution revisited: I. statistical results. Geophys. J. Int., 148(3), 520-541. Doi: 10.1046/j.1365-246x.2002.01594.x.Khan P.K., Ghosh M., Chakraborty P.P., and Mukherjee D., 2011. Seismic b-Value and the Assessment of Ambient Stress in Northeast India. Pure Appl. Geophys., 168(10), 1693-1706. Doi:10.1007/s00024-010-0194-x.Kolathayar S., Sitharam T.G., and Vipin K.S., 2012. Spatial variation of seismicity parameters across India and adjoining areas. Nat Hazards, 60(3), 1365-1379. Doi:10.1007/s11069-011-9898-1.Lomnitz-Adler J., and Lomnitz C., 1979. A modified form of the Gutenberg-Richter magnitude-frequency relation. Bull. Seism. Soc. Am., 69(4), 1209-1214.Marsan D., 2003. Triggering of seismicity at short timescales following Californian earthquakes. J. Geophys. Res., 108, B5, 2266. Doi:10.1029/2002JB001946.Mignan A., 2011. Retrospective on the Accelerating Seismic Release (ASR) hypothesis: Controversy and new horizons. Tectonophysics, 505(1), 1-16. Doi:10.1016/j.tecto.2011.03.010.Mignan A., and Woessner J., 2012. Estimating the magnitude of completeness for earthquake catalogs, Community Online Resource for Statistical Seismicity Analysis. Swiss Seismological Service, ETH Zurich, 145p. Doi:10.5078/corssa-00180805. Available at http://www.corssa.org.Naylor M., Orfanogiannaki, K., and Harte D., 2010. Exploratory data analysis: magnitude, space, and time. Community Online Resource for Statistical Seismicity Analysis, 42p. Doi:10.5078/corssa-92330203. Available at http://www.corssa.org.Ogata Y., and Katsura K., 1993. Analysis of temporal and spatial heterogeneity of magnitude frequency distribution inferred from earthquake catalogues. Geophys. J. Int., 113(3), 727-738. Doi:10.1111/j.1365-246X.1993.tb04663.x.Ogata Y., and Katsura K., 2006. Immediate and updated forecasting of aftershock hazard. Geophys. Res. Lett., 33, 10, L10305. Doi:10.1029/2006GL025888.Rashid H., 1991. Geography of Bangladesh, University Press Ltd, Bangladesh; 2nd edition, 545p.Reimann K.U., 1993. Geology of Bangladesh. Gerbruder Bornt Ramerg, Berlin, Germany, 160p.Siddique S., 2015. Gutenberg-Richter recurrence law to seismicity analysis of Bangladesh. IABSE-JSCE Joint Conference on Advances in Bridge Engineering-III, August 21-22, Dhaka, Bangladesh.Shi Y., and Bolt B.A., 1982. The standard error of the magnitude-frequency b-value. Bull. Seismol. Soc. Am., 72(5), 1667-1687.USGS, 2012. Earthquake Hazards Program. https://earthquake.usgs.gov/earthquakes/search/, USA, retrieved on 20 April 2017.Utsu T., 1999. Representation and analysis of the earthquake size distribution: a historical review and some new approaches. Pure Appl. Geophys., 155(2), 509-535.Wiemer S., and Wyss M., 2000. Minimum magnitude of complete reporting in earthquake catalogs: examples from Alaska, the western United States, and Japan. Bull. Seismol. Soc. Am., 90, 859-869. Doi:10.1785/0119990114.Woessner J., and Wiemer S., 2005. Assessing the quality of earthquake catalogues: Estimating the magnitude of completeness and its uncertainty. Bull. Seismol. Soc. Am., 95(2), 684-698. Doi:10.1785/012040007.Wyss M., Hasegawa A., Wiemer S., and Umino N., 1999. Quantitative mapping of precursory seismic quiescence before the 1989, M7.1 off-Sanriku earthquake, Japan. Annali Di Geoflsica, 42(5), 851-869.Zuniga F.R., and Wyss M., 1995. Inadvertent changes in magnitude reported in earthquake catalogs: Their evaluation through b-value estimates. Bull. Seismol. Soc. Am., 85, 1858-1866..Zuniga F.R., and Wiemer S., 1999. Seismicity patterns: Are they always related to natural causes? Pure Appl. Geophys., 155(2), 713-726.

Nach der dritten Teilung von Polen-Litauen, die gleichzeitig den Untergang der alten Adelsrepublik bedeutete (1795), sowie in der Folge nach den napoleonischen Kriegen, wurde während des Wiener Kongresses (1814-1815) über die Zukunft der polnischen Gebiete im 19. Jahrhundert entschieden. Nach Napoleon Bonaparte wurde der russische Zar Alexander I. zur neuen Hoffnung der Polen, die von der Wiedererrichtung eines unabhängigen Staates träumten. Der Zar herrschte über das russische Teilungsgebiet, das gemäß den Bestimmungen des Wiener Kongresses nun auch als Königreich Polen bzw. „Kongresspolen“ bezeichnet wurde. Die in Wien vereinbarten Grenzen des unter den drei Teilungsmächten Russland, Preußen und Österreich aufgeteilten Landes hatten bis zum Ersten Weltkrieg Bestand. Die „polnische Frage“ während des Wiener Kongresses und ihre weitere Entwicklung nach dem Kongress werden im Band von Historikerinnen und Historikern aus Polen, Österreich, Deutschland und Tschechien erörtert. Abgerundet wird der Band durch ein Kapitel über den Wiener Kongress aus einer der ersten polnisch-sprachigen Beschreibungen Wiens. Diese Beschreibung wurde von Edward Lubomirski (1796-1823), einem Augenzeugen des Kongresses, verfasst. Der junge Lubomirski war während des Kongresses für die Botschaft des Russischen Zarenreichs in Wien tätig. Das letzte Kapitel aus seinem Werk, das 1821 in Warschau publiziert wurde, ist dem Wiener Kongress gewidmet. In dieser Publikation wird es erstmals dem deutschsprachigen Leserpublikum vorgestellt.

State Knowledge and State Building. Descriptive Statistics in Lower Austria 1790–1848. This chapter analyses the Lower Austrian statistical practice at the end of the 18th and in the early 19th century in its broader scientific and administrative context by focusing on the creation of a statistical-topographic collection on the regional level. The collection’s format demonstrates the existence of hitherto unexplored connections between academic Staatenkunde and topography as complementary methods of the contemporary sciences of the state. On the administrative level, the collection highlights the similarly unexplored regional level in statistical data management in the Habsburg Monarchy during the first half of the long 19th century. The changing formats of data collection reveal the process by which regional elites adapted to the cadastral and statistical efforts of the central government during the Franciscan period, as well as its public use. Ultimately, the history of the collection exemplifies the intertwined regional and central levels of state-building, in which the regional participants held considerable infrastructural powers.

Simple thought it appears, there has not been a good protocol for opening an epoxide 1 with a stabilized enolate. Ferdinando Pizzo of the Università di Perugia developed (Tetrahedron Lett. 2010, 51, 1566) a solution to this problem. Masahiro Terada of Tohoku University found (Angew. Chem. Int. Ed. 2010, 49, 1858) that under organocatalysis, the prochiral 4 condensed with aromatic aldehydes with high relative and absolute stereocontrol. Jon T. Njardarson, now at the University of Arizona, showed (Angew. Chem. Int. Ed. 2010, 49, 1648) that the geometry of the epoxide 7 dictated the relative configuration of the product dihydrofuran 8. John P. Wolfe of the University of Michigan devised (Organic Lett. 2010, 12, 1268) conditions for the diastereocontrolled cyclization of 9 to 10. Robert Britton of Simon Fraser University observed (Organic Lett. 2010, 12, 1716) that the microwave-induced closure of 12 proceeded with clean inversion. Christian B. W. Stark of the Universität Leipzig established ( Angew. Chem. Int. Ed. 2010, 49, 1587) that the Ru-mediated oxidative cyclization of 14 to 15 was also highly diastereocontrolled. Two all-trans diastereomers could emerge from the cascade aldol condensation of 16 with an aldehyde. Takashi Yamazaki of the Tokyo University of Agriculture and Technology devised (Organic Lett. 2010, 12, 268) conditions for the selective preparation of either diastereomer. Xuegong She of Lanzhou University uncovered (J. Am. Chem. Soc. 2010, 132, 1788) conditions for the Pt-mediated cyclization of the simple substrate 18 to the tetrahydropyran 19. Michael J. Zacuto of Merck Process established (Organic Lett. 2010, 12, 684) the Ru-catalyzed cyclization of 20 to 21. When an OH was not available, NH insertion was also efficient. Fabien Gagosz of the Ecole Polytechnique Palaiseau devised (J. Am. Chem. Soc. 2010, 132, 3543) the mechanistically distinct Au-mediated cyclization of 22 to 23. Glenn C. Micalizio of Scripps/Florida used (J. Am. Chem. Soc. 2010, 132, 7602) the protocol he had developed to couple 24 and 25 to give a intermediate trisubstituted alkene. Oxidative cleavage of the alkene delivered the ketone, which under acidic conditions cyclized to the spiroketal 26.